Role of angiotensin II and oxidative stress in renal inflammation by hypernatremia: benefits of atrial natriuretic peptide, losartan, and tempol.

Free Radical Research, 2015; Early Online: 1–14 © 2015 Informa UK, Ltd. ISSN 1071-5762 print/ISSN 1029-2470 online DOI: 10.3109/10715762.2015.1006216

REVIEW ARTICLE

Role of angiotensin II and oxidative stress in renal inflammation by hypernatremia: Benefits of atrial natriuretic peptide, losartan, and tempol S. L. Della Penna1, M. I. Rosón1, J. E. Toblli2 & B. E. Fernández1 of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina and 2Laboratory of Experimental Medicine, Hospital Alemán, School of Medicine, University of Buenos Aires, Argentina

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1Department

Abstract The body regulates plasma sodium levels within a small physiologic range, despite large variations in daily sodium and water intake. It is known that sodium transport in the kidneys plays an important role in hypoxia, being the major determinant of renal oxygen consumption. Tubular epithelial cell hypoxia is an important contributor to the development of renal inflammation, and the damage may progress to structural injury, ending in acute renal failure. In this review, we will summarize the renal inflammatory effects of high acute plasma sodium (acute hypernatremia), and the molecular mechanisms involved. We will also discuss recent findings related to the role of oxidative stress and angiotensin II (Ang II) in the pathogenesis of renal injury. We will comment on the effects of agents used to prevent or attenuate the inflammatory response, such as the atrial natriuretic peptide, the superoxide dismutase mimetic – tempol, and losartan. Keywords: hypernatremia, inflammation, oxidative stress, tempol, losartan Abbreviations: a-SMA, alpha-smooth muscle actin; ACE, angiotensin II converting enzyme; Ang II, angiotensin II; ANP, atrial natriuretic peptide; AP1, activator protein-1; ENaC, epithelial sodium channel; HIF-1, transcription factor hypoxia-inducible factor-1; hSGK1, human serum and glucocorticoid-dependent kinase-1; ICAM-1, intercellular adhesion molecule-1; IFN-g, interferon-g; IL-6, interleukin-6; JAK2STAT3, Janus kinase 2-signal transduction activator of transcription 3; JAK-STAT-SOCS1 pathway, Janus-activated kinase - Signal transducers and activators of transcription - Suppressor of cytokines signaling 1 pathway; MCP-1, monocyte chemoattractant protein-1; NADPH oxidase, nicotinamide adenine dinucleotide phosphate-oxidase; NCC, Na-Cl cotransporter; NHE3, sodium–hydrogen exchanger 3; NKCC2, Na-Cl2Cl cotransporter type 2; NO, nitric oxide; pO2, oxygen pressure; Posm, plasma osmolality; RAAS, rennin-angiotensin-aldosterone system; RANTES, regulated on activation, normal T cell expressed and secreted; ROS, reactive oxygen species; TGF-β, transforming growth factor; THAL, thick ascending limb of the loop of Henle; TNa/Qo2, tubular sodium transport/renal oxygen usage ratio; TNa, sodium transport; TNF-α, tumor necrosis factor α; UCP-2, mitochondrial uncoupling protein 2; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor

Introduction Hypernatremia Under normal conditions, plasma sodium levels are regulated within a small physiologic range, despite the large variations in daily sodium and water intake. However, under states of hypernatremia (commonly defined as a plasma sodium concentration greater than 145 mEq.L 1), which occurs when there is an absolute or relative deficit of free water, both the brain and the kidney contribute in concert to restore plasma sodium homeostasis [1–3]. Hypernatremia is generally defined as a plasma sodium concentration greater than 142–148 mEq.L 1, the level depending on the variability of the analyzer and/or the method used for its determination; e.g Dimension, Dade Behring [4]; Modular system, Roche Diagnostic [5]. Brain and kidney responses require the integration of water intake and excretion to be precisely balanced with salt intake and excretion.

Hypernatremia activates neural, cardiovascular, and endocrine adjustments, resulting in hypertension and causing natriuresis until the sodium level is restored. According to the model of Guyton [6], as it occurs in renal failure, primary and secondary hyperaldosteronism, experimental DOCA-salt treatments, etc., the initial blood pressure elevation in response to hypernatremia is due to plasma volume expansion and to an increase in cardiac output. Then, as an autoregulatory compensation for tissue overperfusion, there is a slow shift from high cardiac output to high peripheral vascular resistance to sustain the elevated blood pressure, but no mechanism has been identified. However, recent evidence supports a role for plasma or cerebrospinal fluid high sodium levels as a key mediator of sympathoexcitation, vasopressin release, and elevated blood pressure [7–9]. On the other hand, the increase of plasma sodium induces arterial structural remodeling [10], increases arterial oxidative stress [11], and attenuates endothelial vasodilator responses [12], collagen deposition, and wall thickening, with lumen narrowing [13].

Correspondence: Dr. Silvana L. Della Penna, Department of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956, piso 5. CP1113, Ciudad Autónoma de Buenos Aires, Argentina. Tel: 54-11-4964-8268 E-mail: silvanadellapenna@ gmail.com (Received date: 1 October 2014; Accepted date: 7 January 2015; Published online: 5 March 2015)


2 S. L. D. Penna et al. All of these changes can contribute to the development and/or maintenance of the increased arterial tone and total peripheral vascular resistance, and thus, to the elevated blood pressure. The incidence of hypernatremia is approximately 1% in a general hospital population. An incidence of 10–26% is identified in intensive care unit (ICU) populations [14–16]. Hospital-acquired hypernatremia is frequently not hypovolemic, and some patients may even display signs of volume overload. Hypertonic bicarbonate administration or hypertonic saline administration is among the iatrogenic causes of hypernatremia. Instead, community-acquired hypernatremia is almost always hypovolemic in nature. Causes of excess fluid loss in cases of community-acquired hypernatremia include fever, uncontrolled diabetes mellitus, excessive sweating due to high ambient temperature, osmotic diarrhea, burns, tachypnea, and furosemide-related events. As a rise in plasma osmolality (Posm) is a potent stimulus of thirst that would normally prevent or correct hypernatremia, almost all cases display either impaired thirst (hypodipsia) or impaired access to water [17–19]. The clinical consequences of hypernatremia include insulin resistance, impaired gluconeogenesis, and cardiac dysfunction, in addition to the neurologic consequences. The brain injury that occurs with hypernatremia has been postulated to result in part due to shrinkage of the brain away from the skull, causing mechanical stress on vessels that could lead to hemorrhage and/or ischemia. Hypernatremic patients may display irritation, agitation, lethargy, depressed mental status, and coma. Burn patients who develop hypernatremia have a higher mortality, and there is evidence that the hypernatremia may worsen the burn itself [20].

In this review, we will briefly summarize the renal inflammatory effects of acute hypernatremia and review recent findings related to the role of oxidative stress and the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of renal injury. We will also show the effects of pharmacologic procedures used to prevent or attenuate the inflammatory response to hypernatremia caused by an acute sodium overload, by the administration of natriuretic agents such as the atrial natriuretic peptide (ANP), the inhibition of oxidative stress by the superoxide dismutase (SOD) mimetic, tempol, and the inhibition of the angiotensin II (Ang II) receptor AT1 by the antagonist, losartan. Finally, we discuss some of the putative molecular mechanisms involved in the development of the renal inflammation caused by hypernatremia Figure 1. Hypernatremia and renal inflammation Hypernatremia increases Posm, renal tubular flow, and sodium transport (TNa), contributing to the development of renal inflammation. It is well established that tubular sodium reabsorption is a major determinant of the renal oxygen consumption, and that tubular epithelial cell hypoxia plays an important role in the development of inflammation and structural damage of renal tissues, which may result in acute renal failure [21–23]. The increase of sodium tubular transport, luminal flow, or cytokines, each one or all, may regulate the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which stimulates the production of reactive oxygen species (ROS) [24]. Superoxide anion increases Na-K-2Cl cotransport activity in the thick ascending limb, enhancing further oxidative stress [25]. In this order, it has

Plasma Sodium

Kidney Inflammation /Injury

Sodium Transport Hypertonicity Tubular Flow Hypoxia

Acute Hypernatremia

Acute Renal Failure

Oxidative Stress

Role of

AngII ROS

Mechanisms Involved?

Benefits of

ANP Tempol Losartan

Figure 1. Graphical abstract. The graphical abstract illustrates the mechanisms by which an acute sodium overload and the consequent hypernatremia may cause kidney inflammation and injury, by stimulating the renal angiotensin system and developing oxidative stress. The beneficial effects of atrial natriuretic peptide, the blockade of Angiotensin II–AT1 receptors by losartan, and the inhibition of oxidative stress by tempol, are also mentioned.

Role of angiotensin II and oxidative stress in renal inflammation by hypernatremia 3


been reported that renal hypoxia increases the production of ROS and concomitantly up-regulates the expression of the transcription factor, NF-kB. ROS can activate the mitochondrial uncoupling protein 2 (UCP-2), leading to inefficient renal O2 usage and contributing to renal hypoxia [26]. Hypoxia induces the expression of the transcription factor hypoxia-inducible factor-1 (HIF-1), which coordinates the expression of diverse adaptive genes against hypoxic injury [27,28]. Additionally, HIF-1 transcriptionally up-regulates the expression of soluble growth factors [transforming growth factor b (TGF-b); and vascular endothelial growth factor (VEGF)] [29,30]. TGF-b1, in turn, up-regulates the transcription of the serum and glucocorticoid-dependent kinase hSGK1, involved in the regulation of two important factors for cell volume regulation, the renal epithelial Na channel ENaC, and the thick ascending limb Na, K, and 2Cl cotransporter, NKCC. Recent reports indicate the importance of NF-ĸB activation in the pathophysiology of renal inflammation [31–34], through the generation of pro-inflammatory cytokines as well as adhesion molecules [35]. Furthermore, NF-kB stimulates the angiotensinogen gene in proximal tubules, which is the precursor for local Ang II production [36]. Ang II signal transduction, through AT1 receptor stimulation [37], activates NADPH oxidase and contributes to renal damage through NF-kB [24]. Then, NF-kB can stimulate cytokines, chemokines, and

angiotensinogen gene expression. Increased local Ang II expression enhances the production of superoxide anions by activation of NADPH oxidase [38]. These processes could provide a positive feedback mechanism by which Ang II production is up-regulated. Hong et al. have reported that the increase in NaCl delivery to the thick ascending limb of the loop of Henle (THAL) in the renal medulla is able to stimulate superoxide production by itself, independent of Ang II effects [39]. The authors proposed that an increase in tubular stretch, as a consequence of an increase in tubular fluid filtration after salt loading, may contribute to superoxide generation in the THAL. In turn, superoxide generation may enhance tubular NaCl reabsorption, and thereby, could contribute to enhanced renal hypoxia [40]. On the other hand, it has been described that renal epithelial cells react in the presence of hyperosmolarity, independent of TNa, also increasing ROS production, NF-kB activation and MAPKs signaling mechanisms [41]. In addition, the increase of tubular sodium flow in renal tubular epithelial cells can generate a cascade of events like ROS overproduction, leading to the local activation of NF-kB [39]. Therefore, hypernatremia caused by increasing Posm, tubular flow, stretch and/or increased TNa, contributes to the development of renal inflammation. The main processes that stimulate ROS production and increase oxidative stress and inflammation after a sodium overload are schematized and summarized in Figures 2 and 3.

Hypernatremia Stretch

Osm TNa

Flow

ROS

HYPOXIA

Ang II

HIF-1α NF-kB TGF-β1 Cytokines Adhesion Molecules

Ao

ACE

Figure 2. Mechanism of hypernatremia-induced inflammation. The excess of sodium increases sodium tubular transport (TNa). Higher sodium demand leads to reduced oxygen availability (hypoxia). Hypoxia due to greater sodium transport, together with an increase of tubular flow, stretch, and osmolality, stimulate the formation of reactive oxygen species (ROS). ROS, in turn, up-regulates the expression of diverse molecules such as the transcription factor NF-kB. NF-kB stimulates the angiotensinogen gene (Ao), which is the precursor for local Ang II production (via ACE, Ang II Converting Enzyme). It follows a remarkable increase in the expression of diverse pro-inflammatory genes, which are under the control of NF-kB, including cytokines (TGF-ß1), chemokines, and adhesion molecules; all being molecules involved in pro-inflammatory and pro-fibrotic processes.

4 S. L. D. Penna et al. Sodium overload Tubular Transport Tubular Stretch Tubular Flow

ROS Losartan

Hypoxia

NF-kB ANP


Ang-II

β-actin RANTES

HIF-1α

TGF-α1 ICAM-1

VCAM-1

Pro-INFLAMMATORY Pro-RESPONSE

Tempol

eNOS

HO-1 COX-2

ADAPTATIVE RESPONSE

Figure 3. Protection mechanism on hypernatremia-induced inflammation. As an adaptive response, the hypoxia-inducible factor-1alpha (HIF-1) activates the synthesis of a set of molecules such as the endothelial nitric oxide synthase (eNOS), heme oxygenase-1 (HO-1) and cyclo-oxygenase-2 (COX-2). The inhibition of oxidative stress by the superoxide dismutase mimetic, tempol, and the inhibition of the Ang II-AT1 receptor by the antagonist, losartan, prevent or attenuate the inflammatory response to hypernatremia caused by an acute sodium overload. In addition, inhibitors of sodium reabsorption, such as exogenous ANP, may be useful tools to regulate the expression of key components of the tubulointerstitial inflammation. Red and Blue arrows indicate stimulation and Green arrows indicate inhibition.

Markers of renal inflammation Hypoxia-Inducible Factor-1a HIF-1 is a hypoxia-responsive transcriptional factor that regulates and coordinates the expression of multiple adaptive genes and plays a key role in the cellular response to changes in cellular oxygen tension and hypoxic insult [42,43]. The activation of genes essential to cell survival by HIF-1 is one of the most rapid cellular events taking place during epithelial cell adaptation in order to reduce hypoxia [44,45]. The HIF-1b subunit is generally found to be constitutively expressed, and is not sensitive to changes in oxygen availability, whereas HIF-1a is acutely regulated in response to hypoxia. HIF-1a is more abundantly expressed in the renal medulla, which is relatively hypoxic or under-perfused compared to the cortex, as demonstrated by different authors [46,47]. The RAAS and ACE Recent studies have demonstrated that Ang II is not only generated in the circulation by renin and the angiotensinconverting enzymes, but that it is also locally produced in diverse organs, including the kidneys, vessels, heart, adrenals and brain [48]. The presence of the main components of RAAS allowing Ang II formation has been clearly demonstrated in the kidneys [49]. Early studies have detected renin and its messenger RNA present outside of

the juxtaglomerular cells in the proximal tubules and even in the collecting ducts [50]. The local production of Ang II in renal tissues is generated by tubular epithelial cells or by macrophages, at concentrations that are 100- to 1000-fold higher than that of plasma Ang II. Intrarenal synthesized Ang II is not regulated by systemic hemodynamic changes, but it can amplify circulating Ang II actions, with important implications for the development of cardiovascular diseases [51,52]. Besides its classic actions on the cardiovascular system, tissular Ang II exerts direct paracrine and autocrine effects at the cellular level, influencing cell growth and differentiation, and mediating oxidative stress, inflammation, and fibrosis [53–57]. In the last few years, a large number of experimental studies have further demonstrated a marked influence of local Ang II on renal physiology and diseases, by impairing oxygen balance and stimulating renal inflammation [58]. Ang II remarkably increases the expression of diverse proinflammatory genes that are under the control of the nuclear factors NF-kB and activator protein-1 (AP1). These genes encode for cytokines [interleukin-6 (IL-6); TGF-b1], chemokines [monocyte chemoattractant protein-1 (MCP-1); regulated on activation, normal T cell expressed and secreted (RANTES)], adhesion molecules [vascular cell adhesion molecule-1 (VCAM-1); intercellular adhesion molecule-1 (ICAM-1)], and angiotensinogen, all of them being involved in proliferative, inflammatory and fibrotic processes [59,60]. Based on these observations, Ang II production has been proposed



as a key event of inflammation in the heart, blood vessels, and kidney [61], and therefore its dysfunction has been considered as a therapeutic target [62]. In this way, renal function improves with the use of inhibitors of Ang II synthesis and/or AT1 receptor antagonists and AT2 receptor agonists [63]. The intrarenal RAAS system is able to produce aldosterone as well, which plays an important role in the development of chronic kidney disease. In this way, local renal aldosterone overproduction induces inflammation and matrix formation in the kidneys of diabetic rats. On the other hand, the reduction of aldosterone production improves renal oxidative stress and fibrosis in diabetic rats [64–66]. The RAAS system is one of the main stimulators of synthesis and release of cytokines in the kidney, and at the same time, cytokines are able to stimulate the intrarenal RAAS axis, providing a positive feedback mechanism by which Ang II production is up-regulated. The inflammatory cytokines IL-6, tumor necrosis factor a (TNF-a), and interferon-g (IFN-g), increase angiotensinogen production in renal proximal tubular cells. IFN-g biphasically regulates angiotensinogen expression, via stimulation of the Janus activated kinase - Signal transducers and activators of transcription - Suppressor of cytokines signalling 1 (JAK-STAT-SOCS1) pathway [67]. Additionally, studies performed in the human kidney indicate that IL-6 increases angiotensinogen expression via the STAT3 pathway [68]. However, antipathogenic roles of TNF-a have been also suggested. In this way, TNF-a suppresses angiotensinogen expression in human renal proximal tubule cells [69], suggesting that a negative feedback system mitigates the development of renal injury by acting as a counteracting pathway in the kidney. TGF-ß1 TGF-ß1 is a member of a family of five polypeptides that exerts complex effects on many processes such as organ development, cell growth and differentiation, expression of extracellular matrix and proteins, immune responses, angiogenesis, and tissue repair [70–72]. TGF-ß1 is one of the most important participants in Ang II-mediated matrix synthesis. Experimental studies carried out in rat kidneys have demonstrated that the increase of TGF-ß1 expression is associated with the enhancement of local Ang II and extracellular matrix proteins, being the alterations diminished by the administration of Ang II-converting enzyme (ACE) inhibitors [73–75]. TGF-ß1 activation up-regulates a cellular-volume-sensitive kinase named hSGK1, which in turn, activates epithelial sodium channels (ENaC) [76]. Subsequently, an increase in TNa through ENaC activation is able to promote enhanced cell swelling, which leads to inhibition of proteolysis, increase of protein synthesis, and expansion of excessive extracellular matrix. a-Smooth muscle actin Alpha-smooth muscle actin (a-SMA) is a smooth muscle cell cytoskeleton protein and a marker of

trans-differentiation from fibroblast to myofibroblast [77]. In normal kidneys, a-SMA is present only in the adventitia and vascular media, whereas during a fibrotic process, it is also detected in the renal interstitium [78]. The accumulation of myofibroblasts that express a-SMA leading to extracellular matrix expansion constitutes an early event in interstitial fibrogenesis [79]. In addition, a-SMA is strongly up-regulated by TGF-ß1 in the tubulointerstitial area [80]. RANTES RANTES is a chemokine synthesized by epithelial and endothelial cells, as well as by macrophages. It is known that RANTES, released from stromal cells in damaged tissues, binds to glycosaminoglycans on the endothelium, where it serves as a ‘sign-post’ for the recruitment of immune cells [35]. RANTES (also known as CCL5) is a model chemokine of relevance to a myriad of diseases. Regulation of RANTES expression is complex. Expression of high levels of RANTES is associated with a wide range of immune-mediated diseases, including glomerulonephritis and interstitial nephritis [81]. The importance of RANTES in renal disease was first apparent in a study of renal transplants undergoing rejection [82]. Experimental models of renal inflammation It is known that an acute hypertonic saline overload generates early hypernatremia and plasma volume expansion. Since the sodium ion is largely confined to the extracellular compartment, a hypertonic saline overload in animals without access to drinking water can expand the extracellular fluid space by extracting water from the cells. The intravenous infusion of a hypertonic saline solution to anesthetize rats – which therefore, cannot drink water – is a useful animal model to produce acute hypernatremia [83]. In this animal model, a rapid increase in plasma sodium concentration might produce salt poisoning. The diagnosis of salt poisoning is usually based on the increase of serum sodium concentration above 160 mEq.L 1 [84,85]. However, even though plasma sodium concentration increased as compared with the control group, it remained under 160 mEq.L1. Thus, hypernatremia in this model did not expose these rats to a risk for adverse effects. It must be remarked that there was no hypovolemia, and Posm rose to 326 mOsm.Kg1, a degree that did not exceed the range of mild to moderate dehydration [2]. Furthermore, the animals exhibited increased sodium tubular reabsorption accompanied by preserved glomerular function and tubular morphology [83]. This model allows the study of early alterations such as the increase of absolute sodium tubular reabsorption on tubulointerstitial inflammatory modifications, before functional and/or structural changes appear, damage that would otherwise have been evidenced by decreased creatinine clearance and increased arterial pressure.


6 S. L. D. Penna et al. This animal model of hypernatremia showed increased NF-kB activation and intrarenal Ang II expression. In addition, TGF-ß1 expression in the tubular epithelium and RANTES expression in the tubular epithelium and in the glomerular and peritubular endothelium, were also increased. These patterns represent an early and clear index of acute inflammation and incipient fibrosis. Moreover, a positive staining of a-SMA appeared in the renal peritubular interstitium. These changes constitute evidence that the hypernatremia could be related to the outcome of an inflammatory process in the tubular epithelium. Nevertheless, the influence of an increase of the osmolality on these changes cannot be ruled out. The fact that a moderate degree of intracellular dehydration was observed after sodium overload can be also a cause of inflammation [86,87]. Recent evidences have implicated NF-kB as an important osmosignaling molecule that is activated in the endothelial cells of the renal medulla, in response to hyperosmolarity as well as to dehydration [1,88,98]. Similar results were reported by Eisner et al. [32], who observed that the exposure of cardiomyocytes to hyperosmotic solutions increases the production of free radicals and the NF-kB factor. Furthermore, Chang et al. [89] showed that the increase of free radical concentrations induced the activation of the NF-kB factor in human mesangial cells, and Nemeth et al. described that the activation of NF-kB, and increased the production of proinflammatory chemokines and interleukins in enterocytes incubated with hyperosmotic solution [88,98]. Other authors have also reported that the increase of Posm elicits the increase of NF-kB activity, which generates the production of proinflammatory factors and adhesion molecules, and stimulates genes responsible for local production of Ang II [90,91,98]. The administration of exogenous Ang II worsens renal inflammation after acute sodium overload It is known that Ang II, through the activation of its AT1 receptors, increases TNa in tubular cells and elicits a decrease of oxygen pressure (pO2) and the tubular sodium transport/renal oxygen usage (TNa/Qo2) ratio in the renal cortex; these are two indexes that express the efficiency of the kidney to use the oxygen for chemical reactions [92,93]. Therefore, we hypothesized that Ang II and an overload of sodium simultaneously administered would worsen the inflammatory response produced by a single sodium overload [95]. We analyzed the effects of an acute sodium overload, and the simultaneous infusion of exogenous Ang II, on Ang II expression in the renal cortex and medulla of normal rats. Then, we analyzed its relationship with changes in blood pressure and renal functionality, and the inflammatory response in renal tissues [95]. In this study, we performed the administration of a hypertonic concentration of sodium that did not increase the intrarenal levels of Ang II expression per se. We showed that the hypertonic solution was able to over-express intrarenal Ang II in the glomeruli, vessels, and tubules, when it was infused

together with a low and non-hypertensive dose of Ang II. These additional effects did not depend on blood pressure levels, the degree of dehydration, or hypernatremia. In addition, Ang II increases the production of ROS in renal tissues, via NADPH oxidase stimulation, and in consequence, limits the availability of bioactive nitric oxide (NO) favoring greater TNa, and thus renal hypoxia [94–96]. In addition, NO can react with superoxide to generate the potent oxidant peroxynitrite (ONOO), which has been related to the impairment of renal function and inflammation [99]. On the other hand, Wang et al. and Pathak et al., using the SOD mimetic/peroxynitrite scavenger MnTMPyP [Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin] in rat and mouse models of sepsis, prevented renal cytotoxicity by blocking superoxide and peroxynitrite generation and reversing the impairment of renal function and tubular architecture [100,101]. Current data are consistent with the notion that aldosterone binding to the mineral corticoid receptor is also implicated in the genesis of proximal tubule-related proteinuria and the tubulointerstitial fibrosis, by stimulating the molecular signaling pathway mTOR/S6K1 (rapamycin/S6 kinase 1), and leading to the downstream increase of 3-nitrotyrosine (3-NT) content, a marker for peroxynitrite, the disruption of the catenin-cadherin complex, and to the development of tubulointerstitial fibrosis. The administration of the aldosterone receptor inhibitor spirolactone improved renal biochemical changes, redox status, and structural damage [102]. Additionally, we have reported that under these conditions, the intrarenal expression of TGF-ß1, a-SMA, and NF-ĸB were also enhanced [103]. This report constituted the first demonstration that the administration of a low and non-hypertensive dose of Ang II, which did not significantly alter circulating levels of Ang II, can regulate the expression of renal intratubular Ang II, in the presence of a hypertonic sodium overload. The uptake of circulating Ang II in the kidney by endocytosis, via an Ang II type-1 receptor mechanism, has been consistently demonstrated in diverse animal models, as in Ang II-infused rats [104], Ren-2 transgenic rats, and contralateral (non-clipped) kidneys of 2-kidney, 1-clip rats; the latter a well-known model of hypertension with high levels of circulating Ang II [50,62]. Moreover, the enhancement of intrarenal Ang II exerts positive feedback to augment the intrarenal levels of angiotensinogen mRNA, which further contributes to increased Ang II synthesis. In addition, salt-loading may decrease plasma Ang II in normal [105], Dahl-sensitive and spontaneously hypertensive rats [58,97], while the peptide level is simultaneously increased in the heart and kidneys. These facts strongly suggest that the regulation of local Ang II is independent of systemic Ang II control. Therefore, the enhancement of intrarenal Ang II expression that we observed in our model could result either from the increase of intrarenal Ang II synthesis and/or from the upregulation of tubular AT1 receptors induced by the sodium overload. In turn, this increase can enhance the endocytosis of circulating Ang II. When we analyzed



the distribution of tubular Ang II, we observed that Ang II immunostaining in distal and collector tubules was increased by the infusion of sodium alone or sodium plus Ang II. It is well known that the increase of glomerular filtration rate may enhance angiotensinogen expression, and consequently, Ang II production in proximal tubules [105]. These facts suggest that filtered circulating Ang II and/or local Ang II generated in the proximal tubules and then released into the tubular fluid could act in both cases on distal and collecting tubules, which are precisely the places where we found the highest immunostaining for Ang II. Alternatively, Ang II overexpression in the distal nephron could derive from the angiotensinogen secreted in the proximal tubule and delivered into the tubular lumen, and/or from the renin over-produced in the distal segment [50,106]. The over-expression of intrarenal Ang II in these areas may be linked with Ang II function in these segments. In this way, multiple studies have demonstrated that Ang II regulates the abundance of major renal sodium transporters such as NHE3 (sodium–hydrogen exchanger 3), NKCC2 (Na-Cl-2Cl cotransporter type 2), NCC (Na-Cl cotransporter) and ENaC [107–110]. Another finding from our studies is that in sodium-overloaded rats, the infusion of exogenous Ang II elicited the increment of Ang II immunostaining in proximal tubules, where it can modulate the reabsorption of sodium by the tubular cells [103]. It has been recently reported that the synthesized Ang II in the proximal tubules of rats submitted to sodium overload could be responsible for the increase not only of sodium reabsorption, but of cell hypertrophy in proximal tubules as well [55]. Ang II induces NF-kB activation through the stimulation of the AT1 receptor, which in turn activates the angiotensinogen gene, and thus, Ang II synthesis [72]. Our results suggest that although Ang II exerts physiologic roles, the exacerbated increase of intrarenal Ang II under these conditions could also exert pathologic effects, causing the increase of the oxidative stress, NF-kB activation and proinflammatory and profibrotic cytokine and chemokine expression. Inhibition of renal inflammation produced by hypernatremia ANP The ANP is a regulator of blood pressure and volume homeostasis, with natriuretic and diuretic properties, counterbalancing the activity of the renin-angiotensin-aldosterone system [111–114]. It is known that low doses of ANP exert only natriuretic effects without hypotensive actions, inhibiting the tubular re-absorption of sodium, and in consequence decreasing the demand of oxygen by the renal tubular cells [115]. In contrast, higher doses of ANP are associated with a significant hypotensive effect, which may result in renal hypo-perfusion leading to ischemia, particularly in the renal medulla [116]. Moreover, higher doses of ANP promote pre-glomerular vasodilation and increase the glomerular filtration rate, which in turn,

may increase the re-absorptive work, and consequently, the demand for oxygen [117,118]. Therefore, the administration of ANP, at doses that decrease the blood pressure or increase the glomerular filtration rate, could also contribute to the development of hypoxia and inflammation in the kidney. On the other hand, the increase of local intrarenal Ang II enhances the tubular cell hypoxic response, mediating the activation of NADPH oxidase and the production of superoxide anions in the thick ascending limb cells [119]. These effects were also observed in rat renal medullary homogenates, which were prevented by ANP treatment [120]. Based on these antecedents, ANP may inhibit the production of ROS in an indirect way, counterbalancing the actions of Ang II, thereby protecting the tubular cells from hypoxia and inflammation. It has been demonstrated that ANP, besides its role in the regulation of cardiocirculatory and renal functions, inhibits the production of inflammatory mediators in macrophages, endothelium [120,121], and cardiac myocytes [122]. Therefore, ANP may counterregulate RAAS activity, not only through its natriuretic and vasodilator properties, but also through its anti-inflammatory actions per se. ANP is secreted into the circulation in response to a variety of stimuli, such as the atrial stretch produced by pressure or volume-loading [113]. Chen et al. have reported that a hypoxic exposure increased ANP expression and stimulated ANP release from cultured atrial myocytes in the absence of hemodynamic, renal, or hormonal influences [123]. Interestingly, ANP gene expression is induced in response to hypoxia [124–126]. Moreover, a recent study showed that hypoxia may activate ANP gene promoter activity by the HIF-1a factor, released under these circumstances, through a direct study on the action of HIF-1a on a rat ventricular myoblast cell line [127]. Additionally, it has been described that ANP inhibits the activation of the nuclear factor NF-ĸB [128] by inducing the expression of the NF-kB inhibitor IkB, and the inducible nitric oxide synthase. These two effects contribute to a decrease in the production of peroxynitrites, cytokines and chemokines [129,130]. These findings suggest that, independent of its hemodynamic actions, ANP exerts anti-inflammatory effects, in addition to the the demonstrated inhibitory effects of Ang II on different stages of inflammation and fibrosis in vessels [131] and in the heart [132]. Likewise, in human proximal tubular cells, ANP inhibits cytokine-induced nitric oxide synthesis through a cGMP-independent pathway involving the NPR-C subtype receptor [130]. It has also been demonstrated that ANP inhibits the induction of inflammatory mediators, like the inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), and the TNF-a in macrophages [111]. Recent reports have shown that ANP inhibits hypoxia-induced inflammatory pathways in micro and macrovascular endothelial cells [131]. The potential protective role of ANP has been evaluated in the kidney of hypernatremic rats induced by an acute sodium overload, in order to establish whether the administration of exogenous ANP can suppress the inflammatory response in tubular epithelial cells generated by


8 S. L. D. Penna et al. the overload of tubular sodium. In addition, it may be possible that ANP acts in this sense through the inhibition of NF-kB and Ang II overexpression, observed in this condition [83]. Low doses of ANP, known to exert only natriuretic effects in normal rats and showing non-hypotensive actions, when infused simultaneously with sodium or after sodium infusion, produced diuretic and natriuretic effects prevented and reversed the increase of sodium reabsorption by the renal tubules, and the inflammatory response [129]. This hypernatremic state increased HIF1a expression in the renal medulla. During sodium infusion, as well as later during the recovery period, HIF-1a expression markedly diminished in response to ANP, providing evidences that ANP is capable of protecting the epithelial cell from the hypoxic environment. This protective action of ANP may be related to its direct effects on renal TNa. Since ANP inhibits tubular sodium reabsorption, it reduces cell oxygen demand and thus, cellular hypoxia [124]. These antecedents demonstrate that the early inflammatory response in the kidney, produced by an acute sodium overload, was prevented and reversed by the administration of a low and non-hypotensive dose of ANP. Those effects were associated with a down-regulation of tubular NF-кB, Ang II, and HIF-1a immunoexpression, strongly suggesting that hypoxia was diminished at the level of the tubular cells. Altogether, these antecedents show different mechanisms by which ANP could reduce the inflammatory response, by inhibiting NF-kB and Ang II overexpression. To date, it remains unclear whether any of these mechanisms contribute to the anti-inflammatory effect of ANP. Therefore, ANP treatment may be useful to regulate both the expression of key components of tubulointerstitial inflammation and the oxygen supply/demand relationship in the kidney, mainly at the renal medulla. The protective effects of ANP on sodium-induced inflammation are schematized and summarized in Figure 3. The use of a superoxide dismutase mimetic (Tempol) and an AT1 receptor antagonist (Losartan) To investigate which pathophysiological mechanisms are involved in the early expression of inflammatory markers in renal tissues after an acute sodium overload, Rosón et al. infused rats with an overload of hypertonic sodium, and then treated them with two drugs: (a) the AT1-R antagonist, losartan, to evaluate the renal tubular Ang II signaling pathway, or (b) the permeate SOD mimetic, tempol, to evaluate the participation of the oxidative stress [133]. Tempol (4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-N-oxyl) is a superoxide scavenger commonly used to study the oxidative stress in several rodent models [134,135]. Losartan and tempol were administered by an i.v. infusion, both alone and simultaneously with sodium overload, in order to block renal Ang II effects and to inhibit the oxidative stress production, respectively. The administration of losartan normalized Ang II expression in the sodium-overloaded group, reaching similar levels

as those observed in control animals, but it failed to restore the glomerular filtration rate and HIF-1a immunoexpression, which were found to be increased after the sodium overload. It is well known that several factors, like hyperfiltration, peripheral sympathetic nervous system, or oxidative stress, can regulate angiotensinogen expression, and consequently, Ang II production in the proximal tubules [105,106]. Furthermore, Ang II induces, through its AT1 receptor stimulation, the expression of the gene angiotensinogen, and in consequence, the enhancement of Ang II expression, by a positive feedback mechanism [118]. Additionally, Ang II can be internalized into the cytoplasm and translocated to the nucleus, where it can interact directly with the Ang II receptor located near the nuclear membrane. In this way, specific AT1 receptors have been found at the nuclear membrane, where they induce the transcription of renin and angiotensinogen mRNA, modulating their synthesis [94]. While losartan partially inhibited the hyperfiltration, it normalized Ang II expression, reaching similar levels as those observed in control animals. Thus, it is possible that another cause, independent of the hyperfiltration (evaluated by glomerular filtration rate changes), could be involved in Ang II overexpression, that is, the sympathetic nervous system activity or the stimulated oxidative stress [50]. Independent of the causes that can produce the upregulation of Ang II expression, losartan also normalized NF-kB overexpression and enhanced eNOS expression, but it did not restore HIF-1a overexpression. Thus, another pathway, independent of the up-regulation of renal Ang II, may be responsible for HIF-1a increase in the renal tissues of the hypernatremic rats induced by an acute sodium overload. Moreover, the fact that the administration of losartan decreased Ang II overexpression in the renal tubules and simultaneously increased the natriuresis and sodium fractional excretion, strongly suggests that the increase of renal tubular Ang II after a sodium overload is closely involved in the tubular transport of sodium. Ang II regulates the expression of potent inflammatory factors such as cytokines (TNF-a, MCP-1, and IL-6) and chemokines (RANTES, osteopontin), by stimulating the AT1 receptor [136,137] and the Janus kinase 2-signal transduction activator of transcription (JAK2-STAT3) [138], resulting in inflammation that can be modulated by blockade of the AT1 receptor [139]. However, some reports have shown evidences that AT1 receptor blockage did not suppress the overexpression or the action of proinflammatory cytokines. Molinas et al. have reported that only a high dose of losartan (80 mg.Kg1) is able to prevent the inflammatory response [137]. In addition, in spontaneously hypertensive rats, losartan (20 mg.Kg1) did not affect plasma levels of IL-6 [140]. Furthermore, Grande et al. have reported that AT1R activation stimulates the inflammation and tubulo-interstitial damage associated with obstructive nephropathy [141]. However, AT2 receptor blockade by PD123319 in AT1 receptor KO mice abolished interstitial monocyte infiltration and NF-kB activation, after unilateral ureter obstruction. This suggests that AT2 receptor activation plays a major role as



well, in induced renal inflammation, proving that both receptors may induce the inflammatory response in the kidney. In addition, triiodothyronine (T3)-induced increase of TGF-b1 expression in cardiomyocytes was not changed by AT1 receptor blockade, suggesting that Ang II is not implicated in T3-induced increase of TGF-b expression [142]. Altogether, these antecedents suggest that AT1 receptor blockage does not suppress cytokine production and/or release in all cases. On the other hand, the administration of tempol, together with the sodium overload, scavenged superoxide anion production, normalized Ang II, NF-kB, RANTES, TGF-b1, HIF-1a and eNOS immunoexpression in renal tissues and natriuresis, without affecting mean arterial pressure and the hyperfiltration produced by sodium excess. The fact that tempol normalized HIF-1a and eNOS expression, suggests that the drug attenuates or suppresses the development of oxidative stress induced by the sodium overload in renal tissues. Oxidative stress in renal tissues, which may be produced either by the hyperfiltration or by tubular stretch, may trigger the signaling pathway for the activation of the angiotensinogen-renin-Ang II cascade. In this way, it must be remarked that the administration of tempol reduced Ang II immunostaining in sodiumoverloaded animals, reaching levels similar to those observed in control animals. Although tempol did not affect the glomerular filtration rate, it maintained the hyperfiltration observed in sodium-overloaded animals. These observations reinforce the concept that the hyperfiltration is a direct cause of Ang II over-expression in renal tubules after an acute sodium overload. However, it cannot be excluded that the hyperfiltration may be the cause for the development of oxidative stress, which in turn can activate the Ang II-AT1 receptor cascade. Another possibility for tempol effects on renal Ang II expression may be based on tempol actions on the renal sympathetic system. Considering that the renal sympathetic system stimulates Ang II production [143], tempol, could reduce Ang II synthesis in the renal tubules by inhibiting the nervous system [134,135]. The natriuretic actions exhibited by tempol in the animal model of Rosón et al. [133] are in agreement with those published in other previous reports. It has been shown that tempol increases natriuresis by regulating the activities of the Na-K-ATPase, the Na/H interchanger, the Na-K-2Cl cotransporter, and the ENaC, as well by increasing medullar renal blood flow [134]. Furthermore, tempol prevents the down-regulation of dopamine D1 receptors in proximal tubules of rats submitted to an oxidative stress, leading to a reduction in sodium reabsorption by the proximal tubules [144], which contributes to the enhancement of the natriuresis. However, in the experiments performed by Rosón et al. [133], the administration of both tempol and losartan inhibited TNa and increased the natriuresis, but only tempol decreased the overexpression of the inflammatory markers, suggesting that the beneficial effect of tempol is related to its antioxidant role rather than to its natriuretic effects. In agreement, similar reports have described that the acute response to tempol

administration in anesthetized rats was mainly based on its antioxidant effect, besides the diuretic and natriuretic actions of the drug [134]. Thus, it is possible that another source of superoxide anion may be responsible for the overexpression of the inflammatory markers in the sodium overloaded rats. This process would be independent of the Ang II-AT1 receptor signaling pathway, taking into account that these up-regulations were not suppressed or modified by the administration of losartan. As known, some mechanical factors such as hyperfiltration, tubular epithelial stretch, and/or epithelial TNa, generate oxidative stress, inducing in turn, the overexpression of cytokines and chemokines [145–147]. It has been demonstrated that TGF-b1 is up-regulated by oxidative stress and inhibited by NO [148]. Therefore, superoxide anion upregulation as well as the lower availability of NO may contribute, at least in part, to stimulate the production of TGF-b1. The fact that the addition of tempol, but not of losartan, prevented the increase in TGF-b1 expression in rats subjected to sodium overload, suggests that TGF-b1 over-expression in these animals was likely to be a consequence of the production of oxidative stress, independent of increased Ang II expression in renal tubules. In addition, RANTES overexpression was observed in the collecting ducts, but not in the proximal tubules. Renal interstitial hypertonicity is one of the main causes of the presence of oxidative stress and inflammation [149]. Then, the larger increase of interstitial hypertonicity at the collecting ducts than at the proximal tubules may be related to the presence of a higher expression of RANTES. Furthermore, the overexpression of RANTES was not altered by the administration of losartan, but it was diminished by tempol only at the renal medulla. These results suggest that oxidative stress produced by hypertonicity in the medullary interstice could generate an inflammatory response, as it was described in in vitro studies [149]. The protective effects of losartan and tempol on sodium-induced inflammation are schematized and summarized in Figure 3. Table I describes the current knowledge about the main physiologic and pathophysiologic effects of losartan and tempol. Conclusions The hypernatremia produced by an acute infusion of hypertonic sodium in normal rats is capable of triggering an inflammatory response in the glomeruli, tubular epithelium, and vascular endothelium, and an incipient fibrosis in the tubulointerstitial space. Simultaneously, with the appearance of these alterations, the function of the kidney remains preserved, and renal morphology appears with no abnormalities. The administration of losartan or tempol to these animals has a natriuretic effect, and inhibits the upregulation of Ang II expression in the renal tubules. However, only the administration of tempol prevents the expression of proinflammatory and profibrotic markers. The treatment with tempol, as well as with losartan, inhibits the tubular transport of sodium and increases natriure-

10 S. L. D. Penna et al. Table I. Main effects of losartan and tempol on physiologic and pathophysiologic parameters.*


Blood pressure Glomerular filtration rate Sodium tubular reabsorption Oxidative stress NF-kB activation Cytokines (TNF-a, MCP-1, TGF-b1, IL-8 and IL-6) Chemokines (RANTES, osteopontin) Dopamine D1 receptors Cell hypertrophy Expression of angiotensinogen HIF-1a immunoexpression eNOS expression Peripheral nerve activity

Losartan

Tempol

↓/– [54] ↑/– [101] ↓ [103–106,129] ↓ [54,35] ↓ [54,129] ↓/– [59,132,129,133,134,136–138]

↓/– [9,10,36,130] ↑ [141,130] ↓ [23,129,130] ↓ [9,10,36,130] ↓ [129] ↓ [129,142]

↓/– [62,129,133] ↑ ↓ ↓ ↓ ↑ ↓

[153,155] [35,54] [ 54,48,51,59] [155] / – [131,135] [35,54] [139]

↓ [129] ↓ ↓ ↓ ↓ ↑ ↓

[140] [9] [36] [26,131,135] [143,144,130] [131,130]

*Arrows indicate stimulation or increase (↑) and inhibition or decrease (↓). The scripts (–) indicate absence of effects. References are included between brackets.

sis, but only the administration of tempol decreases the overexpression of the inflammatory markers. Considering this assertion, we suggest that the beneficial effect of the treatment with tempol is related to its antioxidant role rather than to its natriuretic effects. On the other hand, the acute over-expression of local Ang II in renal tubules is linked to the tubular transport of sodium, and consequently, to oxidative stress. It is known that a high concentration of sodium in the extracellular space constitutes a challenge in the normal function of the cells, and in turn, it stimulates an inflammatory response in intestinal, bronchial, and renal epithelial cells [150]. The administration of exogenous ANP in our study may be a useful tool to regulate the expression of key components of tubulointerstitial inflammation, particularly in the renal medulla of the kidney, and to control the oxygen supply or demand, under circumstances of sodium overload. This review demonstrates the adverse inflammatory effects of hypernatremia on the kidney, highlighting the clinical value of controlling hypernatremia or its inflammatory effects. Current questions to be answered in future studies A sustained and extreme hypernatremia can lead to central nervous system dysfunction and death. Considering that Ang II is a direct stimulator of thirst, and that the superoxide anion is involved in the intracellular signaling pathway stimulated by Ang II, it should be noted that the treatment with losartan or tempol may produce impaired thirst sensation, thus worsening hypernatremia. Thus, future studies must be carried out to deepen the knowledge of the effects of RAAS antagonists, scavengers of ROS, or ANP, on the thirst mechanism in experimental models of hypernatremia with access to drinking water. Before the establishment of the putative use of these drugs to improve hypernatremic symptoms in clinical trials, future research might clarify whether the use of these compounds, despite

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Localization and regulation of renal receptors for angiotensin II and atrial natriuretic peptide.

Effects of angiotensin II on atrial natriuretic peptide in pregnancy.

Atrial natriuretic peptide (ANP) as a neuropeptide: interaction with angiotensin II on volume control and renal sodium handling.

Comparison of renal actions of urodilatin and atrial natriuretic peptide.

Modulatory role of angiotensin-II in the secretion of atrial natriuretic factor in rabbits.

Renal disposal of human atrial natriuretic peptide in man.

Inflammation, oxidative stress and renin angiotensin system in atherosclerosis.

Simvastatin attenuates angiotensin II‑induced inflammation and oxidative stress in human mesangial cells.

The renal and vascular effects of central angiotensin II and atrial natriuretic factor in the anaesthetized rat.

Angiotensin-(1-7) relieved renal injury induced by chronic intermittent hypoxia in rats by reducing inflammation, oxidative stress and fibrosis.

Interrelationship of atrial natriuretic peptide, atrial volume, and renal function in premature infants.

Role of Angiotensin II type 1 receptor on renal NAD(P)H oxidase, oxidative stress and inflammation in nitric oxide inhibition induced-hypertension.

Enhancement of renal oxidative stress by injection of angiotensin II into the paraventricular nucleus in renal ischemia-reperfusion injury.

Competitive antagonism of pressor responses to angiotensin II and angiotensin III by the angiotensin II-1 receptor ligand losartan.

Role of atrial natriuretic Peptide in oxytocin induced cardioprotection.

Atrial natriuretic peptide and vasopressin during percutaneous transvenous mitral valvuloplasty and relation to renin-angiotensin-aldosterone system and renal function.

Normal renal sensitivity to atrial natriuretic peptide in Gordon's syndrome.

Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide.

The influence of changes in perfusion pressure and angiotensin II on the renal excretory responses to atrial natriuretic peptides.

Atrial natriuretic peptide (ANP), aldosterone, angiotensin II and renin in the 'low T3 syndrome' in organ donors.

Renal and hemodynamic effects of atrial natriuretic peptide infusion are not mediated by peripheral dopaminergic mechanisms.

Losartan improves measures of activity, inflammation, and oxidative stress in older mice.

Downregulation of natriuretic peptide clearance receptor mRNA in vascular smooth muscle cells by angiotensin II.

Atrial natriuretic peptide.